Synthesis and biochemical evaluation of enzyme inhibitors as potential anti-tumour agents

Adat, Shaheen (2003) Synthesis and biochemical evaluation of enzyme inhibitors as potential anti-tumour agents. (PhD thesis), Kingston University,


Depriving hormone-dependent breast cancer cells of estrogens has been shown to be a beneficial strategy in the treatment of hormone-dependent breast cancer. The enzymes involved in the biosynthesis of estrogens include: 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD), aromatase (AR) and estrone sulfatase (ES). The latter two have been the target of intensive research within our group. Within the current project, we report the synthesis of various types of compounds as potential inhibitors of AR in an effort to determine detailed information regarding the active site of this enzyme; we have also attempted to combine our knowledge of AR and ES in the development of compounds which are able to ihhibit both enzymes. In the first series of compounds to be investigated, compounds were synthesised based on enantiomerically pure forms of the "Evans chiral auxiliary", which is commercially available in both the R and S forms. The oxazolidinone and the phenyl ring systems were derivatised so as to produce N-alkylated compounds which contained a phenylamine moiety for ligating to the Fe of the cytochrome P-450 haem. The compounds were evaluated using a standard literature assay and were, in general, found to be equipotent or more potent than the standard compound aminoglutethimide (AG), with the most potent inhibitor being the pentyi derivative of the R-form (IC50=0.B3±O.05¡..tM). An interesting and different trend was observed 'within the inhibitors based on the S-enantiomer, which were found to be weak inhibitors of AR in comparison to AG - the most potent compound (55) was found to possess an IC50 value of 16.82±0.20¡..tM. The inhibitory activities of both the R- and S-forms were rationalised using the novel substrate-haem complex (SHC) approach. 'From the rationalisation of the inhibitory activity of the oxazolidinone based compounds, the importance of the C(17) position of the steroid backbone was highlighted. As such, we undertook the synthesis and biochemical evaluation of a series of esters based on testosterone. On undertaking the biochemical evaluation of these compounds it was discovered that testosterone possessed potent inhibitory activity (IC50=20.6±O.15¡..tM), and that of the esters, testosterone acetate was shown to have an IC50 value of 4B.7±O.07¡..tM, whereas testosterone decanoate possessed an IC50 value of 164.1±O.5¡..tM. However, the derivatisatian of the alkyl to an aryl carboxylate moiety resulted in one compound which was found to possess highly potent inhibitory activity. That is, testosterone 4-nitrobenzoate was found to possess an IC50 value of B.5±0.05¡..tM. In an effort to synthesise dual inhibitors of AR and ES, we undertook the synthesis of compounds based on the results of our previous studies into ES and the inhibitory activities observed within the testosterone and oxazolidinone based compounds. 'In particular, an attempt was made to incorporate the structural aspects of anastrozole (an aromatase inhibitor) together with a sulfonated phenyl moiety. We synthesised a series of azole based compounds and as expected, these compounds were found to be potent inhibitors of AR, the most potent [1-(4-chloro-benzyl)-1 H-imidazole (BO)] was found to possess an IC50 value of 70±0.5nM. However, the synthesis of the sulfonated compounds proved troublesome and as such no inhibitory data was obtained for these compounds.

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